The threshold level of urinary cadmium associated with increased urinary excretion of retinol-binding protein and β2-microglobulin: a re-assessment in a large cohort of nickel-cadmium battery workers

OBJECTIVE: To evaluate the threshold value of urinary cadmium (CdU) for renal dysfunction on the basis of relationships unconfounded by protein degradation, diuresis and the renal effects associated with chronic smoking. Methods We studied 599 workers (451 men, mean age 45.4 years) who were employed in four nickel-cadmium battery plants for 18.8 years on average. After adjustment for covariates by multiple regression, the CdU threshold values for increased concentrations of retinol-binding protein (RBPU) and b(2)-microglobulin (b(2)-mU) were assessed by logistic regression and benchmark dose analyses using as referents workers with CdU10, respectively. The benchmark dose (BMD5) and the benchmark dose lower limit (BMDL5) for a 5% excess in the background prevalence of abnormal RBPU and b(2)-mU were estimated at 5.1/3.0 and 9.6/5.9. When excluding ever smokers, odds for abnormal RBPU and b(2)-mU were both increased only among workers with CdU>10 (OR, 21.8, 95% CI, 6.4-74.4 and OR, 15.1, 95% CI, 3.6-63.1, respectively). In never smokers, these BMD5/BMDL5 of CdU were estimated at 12.6/6.6 and 12.2/5.5 while in ever smokers they were 6.2/4.9 and 4.3/3.5. Conclusions On the basis of associations undistorted by smoking and adjusted for covariates, the BMDL5 of CdU for low-molecular-weight proteinuria induced by occupational exposure to Cd can be reliably estimated between 5.5 and 6.6 μg/g creatinine

The c.429_452 duplication of the ARX gene: a unique developmental-model of limb kinetic apraxia:

BACKGROUND: The c.429_452dup24 of the ARX gene is a rare genetic anomaly, leading to X-Linked Intellectual Disability without brain malformation. While in certain cases c.429_452dup24 has been associated with specific clinical patterns such as Partington syndrome, the consequence of this mutation has been also often classified as "non-specific Intellectual Disability". The present work aims at a more precise description of the clinical features linked to the c.429_452dup24 mutation. METHODS: We clinically reviewed all affected patients identified in France over a five-year period, i.e. 27 patients from 12 different families. Detailed cognitive, behavioural, and motor evaluation, as well as standardized videotaped assessments of oro-lingual and gestural praxis, were performed. In a sub-group of 13 ARX patients, kinematic and MRI studies were further accomplished to better characterize the motor impairment prevalent in the ARX patients group. To ensure that data were specific to the ARX gene mutation and did not result from low-cognitive functioning per se, a group of 27 age- and IQ-matched Down syndrome patients served as control. RESULTS: Neuropsychological and motor assessment indicated that the c.429_452dup24 mutation constitutes a recognizable clinical syndrome: ARX patients exhibiting Intellectual Disability, without primary motor impairment, but with a very specific upper limb distal motor apraxia associated with a pathognomonic hand-grip. Patients affected with the so-called Partington syndrome, which involves major hand dystonia and orolingual apraxia, exhibit the most severe symptoms of the disorder. The particular "reach and grip" impairment which was observed in all ARX patients, but not in Down syndrome patients, was further characterized by the kinematic data: (i) loss of preference for the index finger when gripping an object, (ii) major impairment of fourth finger deftness, and (iii) a lack of pronation movements. This lack of distal movement coordination exhibited by ARX patients is associated with the loss of independent digital dexterity and is similar to the distortion of individual finger movements and posture observed in Limb Kinetic Apraxia. CONCLUSION: These findings suggest that the ARX c.429_452dup24 mutation may be a developmental model for Limb Kinetic Apraxia

The significance of the associations between biomarkers of renal effects and cadmium at low environmental exposure

In this thesis work, we evaluate the current risk assessment methodology for cadmium (Cd), which is largely based on studies among populations with high environmental or industrial exposure to the metal. Basically the methodology relies on the dose-response analysis between the urinary excretion of Cd (U-Cd), used as indicator of Cd body burden, and of low-molecular-weight (LMW) proteins used for screening Cd-induced tubular dysfunction. The threshold for Cd toxicity of 10 µg/g creatinine established 30 years ago was confirmed in a cross-sectional study on a large group of industrial workers. Because of the renal effects of smoking unrelated to Cd, dose-response relationships between U-Cd and LMW proteins in urine are shifted to lower U-Cd values, despite the adjustment for cumulative exposure to tobacco smoke. We therefore suggested that the true Cd threshold for renal dysfunction might be derived after exclusion of smokers only. Using the benchmark dose (BMD) approach with associations undistorted by smoking, we estimated the Cd threshold value for a 5% excess in the background prevalence of abnormal LMW proteins around 9.5 µg/g creatinine with a lower confidence limit between 4.2 and 1.7 µg/g creatinine, for U-RBP and U-β2M, respectively. In a large sample of adolescents with very low environmental exposure, we observed similar significant associations between Cd and LMW proteins in urine with no evidence of threshold. The causality of these associations observed at low exposure levels has been questioned. We proposed a mechanism of co-excretion between Cd bound to metallothionein (MT) and the LMW proteins sharing the same tubular binding sites. Therefore, these associations might be unrelated to Cd-toxicity and simply reflect the physiological variations in the renal uptake capacity of proteins affecting Cd-MT and LMW proteins in the same direction. The urinary excretion of Cd was modeled as a function of age in different age-groups from the general Belgian population. We showed that, over lifetime, U-Cd followed a non-monotonous and nonlinear increase with age with large interindividual variations unlikely to reflect parallel variations in the body burden of the metal. Our findings suggest that at these low exposure levels, U-Cd variations are mainly driven by physiological factors influencing the intake and the renal elimination of the metal. In conclusion, this thesis challenges the current paradigm for the Cd health risk assessment when using U-Cd as marker of the Cd body burden in populations with low-level exposure to the metal. The potential influence of confounding factors on biomarkers variations might lead to an overestimation of health risks of environmental Cd. These findings deserve careful consideration before inferring causation and establishing threshold values from epidemiological studies using U-Cd as exposure indicator.(MED 3) -- UCL, 201

Interactions between domestic water hardness, infant swimming and atopy in the development of childhood eczema.

Our study shows that exposure to hard water and infant swimming interact with atopic status to increase the prevalence of childhood eczema. A breaching of the epidermal barrier by detergents or salts in hard water and by chlorine-based oxidants in swimming pool water might explain these interactions

Characterization of deep infiltrations in subsurface drained agricultural system

International audienceSubsurface drainage practice is widely used in agriculture to eliminate temporary winter waterlogging of hydromorphic soils. Soil surface saturation is mainly due to the presence of an underlying layer (~1m deep) with a high clay content, considered as semi-impermeable. Generally, deep infiltration under this layer has been neglected in many hydrological studies. However, considering the variations in the ground water table levels, the recharge is mainly due to the deep infiltration. Understanding the dynamic of this infiltration is very important both for the quantitative management of groundwater resources and for the protection of its quality. Indeed, this infiltration can transfer spreading products (fertilizers and pesticides) used in agriculture, mainly the water-soluble molecules. To understand the dynamic of the deep infiltration, hydrological and geophysical monitoring using ERT (Electrical Resistivity Tomography) method was set up on the drained experimental plot of Boissy le Châtel (Orgeval Observatory, in France). The water balance at the scale of the experimental plot highlighted the contribution of the deep infiltration to the groundwater table rise at the beginning of fall season. Time-lapse geophysical survey coupled with water content monitoring on a 1.5m vertical profile showed the movement of a rewetting front from the soil surface towards deep layers during this very short transition period, which follows a precipitation event. After this period, during the intense drainage season, the deep infiltration below the drains continues (in the order of 0.12 mm/day compared to 2mm/day for subsurface drained flow) despite the rise of the water table to the surface layer. However, it is difficult to monitor its pathway using the passive ERT method, less sensitive to electrical resistivity variations in the range of soil water content close to saturation

Serum levels of club cell secretory protein (Clara) and short- and long-term exposure to particulate air pollution in adolescents

Background: Studies in populations have shown that particulate air pollution is associated with changes in lung function in adolescents. Objective: We investigated the effect of short- and long-term exposure to particulate matter (PM10) on the pulmonary health of adolescents, using serum lung club cell secretory protein (Clara) (CC16) as a biomarker for respiratory epithelium integrity..

Anti-Argonaute antibodies as a potential biomarker in NMOSD

Background and objectives: Neuromyelitis optica spectrum disorders (NMOSDs) are a group of diseases mainly characterised by recurrent optic neuritis and/or myelitis. Most cases are associated with a pathogenic antibody against aquaporin-4 (AQP4-Ab), while some patients display autoantibodies targeting the myelin oligodendrocyte glycoprotein (myelin oligodendrocyte glycoprotein antibodies (MOG-Abs)). Anti-Argonaute antibodies (Ago-Abs) were first described in patients with rheumatological conditions and were recently reported as a potential biomarker in patients with neurological disorders. The aims of the study were to investigate if Ago-Abs can be detected in NMOSD and to evaluate its clinical usefulness. Methods: Sera from patients prospectively referred to our centre with suspected NMOSD were tested for AQP4-Abs, MOG-Abs and Ago-Abs with cell-based assays. Results: The cohort included 104 prospective patients: 43 AQP4-Abs-positive cases, 34 MOG-Abs positive cases and 27 double-negative patients. Ago-Abs were detected in 7 of 104 patients (6.7%). Clinical data were available for six of seven patients. The median age at onset of patients with Ago-Abs was 37.5 [IQR 28.8-50.8]; five of six patients tested positive also for AQP4-Abs. Clinical presentation at onset was transverse myelitis in five patients, while one presented with diencephalic syndrome and experienced a transverse myelitis during follow-up. One case presented a concomitant polyradiculopathy. Median EDSS score at onset was 7.5 [IQR 4.8-8.4]; median follow-up was 40.3 months [IQR 8.3-64.7], and median EDSS score at last evaluation was 4.25 [IQR 1.9-5.5]. Conclusion: Ago-Abs are present in a subset of patients with NMOSD and, in some cases, represent the only biomarker of an autoimmune process. Their presence is associated with a myelitis phenotype and a severe disease course